WO2022028264A1 - Pilule enrobée entérique de fumarate d'obizidine, son procédé de préparation et son utilisation - Google Patents

Pilule enrobée entérique de fumarate d'obizidine, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2022028264A1
WO2022028264A1 PCT/CN2021/108360 CN2021108360W WO2022028264A1 WO 2022028264 A1 WO2022028264 A1 WO 2022028264A1 CN 2021108360 W CN2021108360 W CN 2021108360W WO 2022028264 A1 WO2022028264 A1 WO 2022028264A1
Authority
WO
WIPO (PCT)
Prior art keywords
enteric
coated
fumarate
weight
oxidazine
Prior art date
Application number
PCT/CN2021/108360
Other languages
English (en)
Chinese (zh)
Inventor
程立仁
Original Assignee
深圳市真兴医药技术有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳市真兴医药技术有限公司 filed Critical 深圳市真兴医药技术有限公司
Priority to EP21853332.1A priority Critical patent/EP4193991A1/fr
Priority to JP2023532638A priority patent/JP7448275B2/ja
Publication of WO2022028264A1 publication Critical patent/WO2022028264A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine and chemical industry, and in particular, relates to an enteric-coated oxidazine fumarate pellet, a preparation method thereof, and its use in the preparation of an antitumor drug for prevention and/or treatment.
  • Obitrazine fumarate chemical name (4-benzyl-[1,4]diazepan-1-yl)-acetyl(3-allyl-2-hydroxy-methylenebenzene) Hydrazine fumarate, the chemical structure is as follows:
  • the inventor of the present application has carried out a large number of experimental studies on the formulation and preparation process of oxidazine fumarate, and developed an enteric-coated pellet formulation of oxbitzine fumarate.
  • Obitrazine has good compatibility, and the preparation has good stability and high safety, and can be rapidly disintegrated and released smoothly in intestinal fluid, thereby improving the bioavailability of oxbitzine fumarate.
  • the enteric-coated pellets adopt the extrusion spheronization process to prepare the drug-containing pellets, which is conducive to expanding the drug-loading range of the pellets, facilitates the adjustment of the dosage specifications of the pellets according to clinical needs, and realizes industrialized production, and at the same time, the time-consuming is short and the effect is good.
  • the first aspect of the present invention provides an enteric-coated pellet of oxidazine fumarate; the second aspect of the present invention provides a capsule or tablet containing the enteric-coated pellet; the third aspect of the present invention provides a A method for preparing the enteric-coated pellets; the fourth aspect of the present invention provides the use of the enteric-coated pellets or the capsules or tablets in preparing a medicament for preventing and/or treating tumors.
  • a fifth aspect of the present invention provides the enteric-coated pellets or the capsules or tablets for preventing and/or treating tumors.
  • a sixth aspect of the present invention provides a method for treating tumors, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the enteric-coated micropellets or the capsules or tablets.
  • the first aspect of the present invention provides an enteric-coated pellet, which comprises a) a pellet core containing oxidazine fumarate, b) an isolation layer and c) an enteric layer.
  • the pellet core further comprises a diluent, a disintegrant and a co-solvent.
  • the diluent is selected from one or more of microcrystalline cellulose, lactose, and pregelatinized starch.
  • the diluent is microcrystalline cellulose.
  • the diluent is lactose.
  • the diluent is pregelatinized starch.
  • the disintegrant is one or more selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone kind.
  • the cosolvent is one or more selected from surfactants such as polyvinylpyrrolidone, Tween-20, Tween-60, Tween-80, and sodium lauryl sulfate. kind.
  • the cosolvent is polyvinylpyrrolidone.
  • the co-solvent is Tween-20.
  • the co-solvent is Tween-60.
  • the co-solvent is Tween-80.
  • the co-solvent is sodium lauryl sulfate.
  • the co-solvent is a combination of polyvinylpyrrolidone and Tween-20.
  • the diluent in the pellet core is one or more selected from microcrystalline cellulose, lactose and pregelatinized starch; the disintegrant is selected from sodium carboxymethyl starch, cross-linking One or more of sodium carboxymethyl cellulose and crospovidone; cosolvent is selected from polyvinylpyrrolidone, Tween-20, Tween-60, Tween-80, sodium lauryl sulfate one or more of.
  • the disintegrant is:
  • the disintegrant is: sodium carboxymethyl starch.
  • the disintegrant is: Croscarmellose sodium.
  • the disintegrant is: crospovidone.
  • the disintegrant is a combination of low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.
  • the mass ratio of the low-substituted hydroxypropyl cellulose to sodium carboxymethyl starch is 0.1-3.5:1 , such as 0.5:1, 1:1, 1.4:1, 1.5:1, 1.75:1, 2:1, 2.3:1, 2.5:1, or 3:1.
  • the disintegrant is a combination of low-substituted hydroxypropyl cellulose and croscarmellose sodium.
  • the mass ratio of the low-substituted hydroxypropyl cellulose and croscarmellose sodium 0.1 to 3.5:1, such as 0.5:1, 1:1, 1.4:1, 1.5:1, 1.75:1, 2:1, 2.3:1, 2.5:1, or 3:1.
  • the disintegrant is a combination of low-substituted hydroxypropyl cellulose and crospovidone.
  • the mass ratio of the low-substituted hydroxypropyl cellulose and crospovidone is 0.1-3.5:1 , such as 0.5:1, 1:1, 1.4:1, 1.5:1, 1.75:1, 2:1, 2.3:1, 2.5:1, or 3:1.
  • the pellet core comprises: in parts by weight
  • the pellet core comprises: in parts by weight
  • the pellet core comprises: in parts by weight
  • the isolation layer comprises isolation material
  • the isolation layer further includes an anti-sticking agent.
  • the insulating material is one or two selected from the group consisting of hydroxypropyl methylcellulose and hydroxypropyl cellulose.
  • the release material is hydroxypropyl methylcellulose.
  • the release material is selected from hydroxypropyl cellulose.
  • the release material is a combination of hydroxypropyl methylcellulose and hydroxypropyl cellulose.
  • the anti-sticking agent in the release layer is talc.
  • the enteric layer comprises an enteric material
  • the enteric layer further includes a plasticizer and/or an anti-sticking agent.
  • the enteric material is a member selected from the group consisting of acrylic resin, hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and cellulose acetate phthalate. one or more.
  • the enteric material is an acrylic resin.
  • the enteric material is hydroxypropyl methylcellulose acetate succinate.
  • the enteric material is hypromellose phthalate.
  • the enteric material is cellulose acetate phthalate.
  • the plasticizer is triethyl citrate.
  • the anti-adherent agent in the enteric layer is talc or glycerol monostearate or a combination of the two.
  • the anti-adherent in the enteric layer is talc.
  • the anti-adherent in the enteric layer is glycerol monostearate.
  • the anti-adherent in the enteric layer is a combination of talc and glycerol monostearate.
  • the enteric-coated micropellets wherein a) the pellet core containing oxidazine fumarate, b) the isolation layer and c) the mass percentage of the enteric-coated layer are as follows:
  • the enteric-coated micropellets wherein a) the pellet core containing oxidazine fumarate, b) the isolation layer and c) the mass percentage of the enteric-coated layer are as follows:
  • the enteric-coated pellets wherein the weight of the isolation layer is 10%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the isolation layer is 14%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the isolation layer is 14%-18% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the isolation layer is 14%-16% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the enteric-coated layer is 16%-26% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the enteric-coated layer is 16%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the enteric-coated layer is 17%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets wherein the weight of the enteric-coated layer is 18%-20% of the weight of the pellet core containing oxidazine fumarate.
  • the enteric-coated pellets comprise: in parts by weight
  • the enteric-coated pellets comprise: in parts by weight
  • the enteric-coated micropellets are between 0.3-1.5 mm in size.
  • the enteric-coated pellets wherein the oxidazine fumarate is amorphous, crystalline form A or crystalline form B.
  • the particle size D90 of the oxidazine fumarate particles in the enteric-coated pellets is less than or equal to 50 ⁇ m.
  • the particle size D90 of the oxidazine fumarate particles in the enteric-coated pellets is less than or equal to 30 ⁇ m.
  • the second aspect of the present invention provides a capsule or tablet, which is made of the enteric-coated micropellet described in any of the foregoing embodiments of the present invention in a canned capsule or by tableting.
  • the content of oxidazine fumarate in the capsule or tablet is 0-200 mg.
  • the amount of oxidazine fumarate in the capsule or tablet is 5 mg, 10 mg, 25 mg, 50 mg, 100 mg or 200 mg.
  • a third aspect of the present invention provides a preparation method of enteric-coated pellets, which comprises the following steps:
  • Obitrazine fumarate is mixed with diluent, disintegrating agent to obtain premix;
  • the premix is a mixture of the co-solvent and ethanol having a concentration of 50% to 70% (preferably 55% to 65%, such as 60%) Obtained after mixing the aqueous solution;
  • the fourth aspect of the present invention provides the use of the enteric-coated pellets or the capsules or tablets in the preparation of a medicament for preventing and/or treating tumors.
  • a fifth aspect of the present invention provides the enteric-coated pellets or the capsules or tablets for preventing and/or treating tumors.
  • a sixth aspect of the present invention provides a method for treating tumors, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the enteric-coated micropellets or the capsules or tablets.
  • the tumor is acute promyelocytic leukemia, large cell lung cancer, liver cancer, or non-small cell lung cancer.
  • mass percent refers to the weight of the individual components in the formulation divided by the total weight of all components of the formulation and then multiplied by 100%.
  • % refers to mass percentage unless otherwise specified.
  • D90 refers to the particle size at which the cumulative particle size distribution number of a sample reaches 90%. Its physical meaning is that particles with a particle size smaller than it account for 90%, for example, "D 90 is less than or equal to 50 ⁇ m” means “90% particles with a particle size not greater than 50 ⁇ m”.
  • AUCo - ⁇ refers to the area under the concentration time curve (AUC) when extrapolated to infinity or the AUC+ (last assay concentration/elimination rate constant) to the last assay time point.
  • Cmax is defined as the measured maximum plasma concentration of the active ingredient.
  • compositions provided by the present invention can be administered to patients alone, or can be co-administered or combined with other active formulations.
  • co-administration and “combination” include the simultaneous or sequential administration of two or more therapeutic agents without a specific time limit.
  • the agents are present in a cell or in an individual at the same time, or exert a biological or therapeutic effect at the same time.
  • each therapeutic agent is in the same composition or unit dosage form. In other embodiments, each therapeutic agent is in a different composition or unit dosage form.
  • prior to administration of the second therapeutic agent eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks ago
  • administration of the first agent e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after
  • diluent includes, but is not limited to, microcrystalline cellulose, lactose, compressible sugars, dextrose, mannitol, dextrin, maltodextrin, sorbitol, xylitol, sodium chloride, calcium carbonate, Magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, kaolin, powdered cellulose, pregelatinized starch, starch, barium sulfate, magnesium trisilicate, aluminum hydroxide, and combinations thereof.
  • the diluents described herein include at least microcrystalline cellulose.
  • the diluent of the present invention comprises microcrystalline cellulose and one selected from the group consisting of mannitol, lactose, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch, sucrose, or variety.
  • disintegrant includes, but is not limited to, corn starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, croscarmellose sodium, crospovidone (cross-linked polyvinylpyrrolidone) Vidone, PVP), alginic acid, sodium alginate and guar gum, etc.
  • co-solvent includes, but is not limited to, sodium benzoate, citric acid, calcium lactate, ethanol, isooctyl alcohol, polyvinylpyrrolidone, Tween-20, Tween-60, Tween-80, sodium lauryl sulfate Wait.
  • the enteric-coated pellet preparation of oxidazine fumarate provided by the invention has good compatibility with the selected excipients and oxidazine fumarate, and has good preparation stability and high safety, and can be rapidly disintegrated in intestinal fluid. , stable release, thereby improving the bioavailability of oxidazine fumarate.
  • the enteric-coated pellets adopt the extrusion spheronization process to prepare the drug-containing pellets, which is conducive to expanding the drug-loading range of the pellets, facilitates the adjustment of the dosage specifications of the pellets according to clinical needs, and realizes industrialized production, and at the same time, the time-consuming is short and the effect is good.
  • rpm refers to revolutions per minute
  • RRT refers to relative retention time
  • min refers to minutes
  • ND refers to no detection
  • DCPA refers to anhydrous calcium hydrogen phosphate
  • MCC PH200 refers to microcrystalline cellulose PH200
  • SDS refers to dodecyl Sodium sulfate
  • HPMC-AS refers to hydroxypropyl methylcellulose acetate succinate
  • HPMCP refers to hypromellose phthalate
  • API refers to oxbitzine fumarate
  • SD refers to standard deviation.
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • Obitrazine fumarate was purchased from Dongguan Changan Dongyang Pharmaceutical Research and Development Co., Ltd.
  • microcrystalline cellulose was purchased from Asahi Kasei, Japan
  • sodium carboxymethyl starch was purchased from Anhui Shanhe Accessories Co., Ltd.
  • low-substituted hydroxypropyl cellulose was purchased from Anhui Shanhe Accessories Co., Ltd.
  • Tween 20/Tween 80 were purchased from Nanjing Weir Chemical
  • polyvinylpyrrolidone (k30) was purchased from Ashland
  • pregelatinized starch was purchased from Roquette
  • hydroxypropylmethyl cellulose ( E3) was purchased from Anhui Shanhe Accessories Co., Ltd.
  • talc was purchased from Guangxi Longsheng Huamei Talc Development Co., Ltd.
  • Obitrazine fumarate raw material is passed through YK-60 equipment rocking granulator (Changsha Yi Pharmaceutical Machinery Co., Ltd.), passed through a 24-mesh sieve, and pretreated for standby;
  • mix soft materials weigh 1125.10g of pretreated raw materials, 625.12g of microcrystalline cellulose, 200.20g of sodium carboxymethyl starch, and 350.32g of low-substituted hydroxypropyl cellulose and add them to a wet granulator (Shenzhen Xinyite Technology Co., Ltd.), mix for 5 minutes under the condition that the rotating speed of the stirring paddle is 1-3 rps and the rotating speed of the cutting knife is 10-40 rps.
  • a wet granulator Shenzhen Xinyite Technology Co., Ltd.
  • extrusion spheronization the soft material prepared in the second step is extruded through an orifice plate of 0.3 to 1.5 mm using an extrusion spheronizer (Shenzhen Xinyite Technology Co., Ltd.) The spheronization is carried out at low speed (100-500rpm). The high-speed spheronization time and the low-speed spheronization time are adjusted according to specific conditions. During the spheronization process, an appropriate amount of 60% to 95% ethanol can be sprayed to help the pellets form.
  • drying the pellets (wet material) prepared by spheronization are dried in a fluidized bed (Shenzhen Xinyite Technology Co., Ltd.), the air inlet temperature is 45°C, the material temperature is controlled at 35-45°C, and the drying time is about 30min .
  • Preparation of coating solution Heat purified water of about 1/2 of the recipe amount to about 60°C, stir into a vortex, slowly add 241.12g of hydroxypropyl methylcellulose to disperse, add the remaining purified water (room temperature), stir until The solution was clarified, and then talc was added and stirred for 30 min for later use.
  • Coating Put the plain pellets into the fluidized bed, set the fan speed to 1750 ⁇ 2000rpm, set the inlet air temperature to 40 ⁇ 50°C, which can be adjusted according to the actual situation, preheat the pellets, control the material temperature to 37 ⁇ 39°C and then start the atomization
  • the pressure is 0.13-0.18Mpa
  • the peristaltic pump is turned on to start spraying, the speed of spraying is increased from slow to slow, and the speed of the peristaltic pump is controlled to 8-12rpm (inner diameter of the tube is 5mm). parameters to prevent pellet sticking.
  • Preparation of coating solution stir the weighed absolute ethanol into a vortex and slowly add 227.02g of hydroxypropyl methylcellulose acetate succinate to swell, slowly add purified water (cold water), stir until the solution is clear, and then add talc in turn Powder, triethyl citrate and glyceryl monostearate, stir for 30min for subsequent use;
  • Coating Put the isolation coat pellets into the fluidized bed (Shenzhen Xinyite Technology Co., Ltd.), set the fan speed to 1850 ⁇ 2200rpm, and the inlet air temperature to 42 ⁇ 49°C, preheat the pellets, and control the material temperature to 36 ⁇ 41°C. Turn on the atomization pressure of 0.11-0.18Mpa, turn on the peristaltic pump to start spraying, the speed of spraying is accelerated from slow to slow, and the speed of the peristaltic pump is controlled to 8-12rpm (the inner diameter of the tube is 5mm). Adjust the parameters according to the actual situation to prevent the pellets from sticking.
  • Capsule filling is carried out after determining the amount of capsules according to the content of enteric-coated pellets. Loading capacity: theoretical value ⁇ 5%, loading difference: ⁇ 7.5%.
  • Stability investigation method Under the conditions of 40 ⁇ 2°C and 75 ⁇ 5%RH, samples were taken in the 0th, 1st, 2nd and 3rd months to detect the related substances, acid resistance and release degree.
  • the specific detection method is as follows:
  • enteric-coated pellet preparation prepared in this example (approximately equivalent to 65mg of oxidazine fumarate), accurately weigh it, place it in a 25ml measuring bottle, add an appropriate amount of diluent (DMSO-methanol (1:4v/v) )) ultrasonication for 15min to dissolve oxidazine fumarate, let cool, dilute to volume with diluent, shake well, centrifuge at 12000rpm for 10min, and take the supernatant as the test solution. Precisely measure 1ml of the test solution and put it in a 100ml volumetric flask, dilute it to the mark with diluent, shake well, and use it as a control solution.
  • DMSO-methanol (1:4v/v) diluent
  • oxbitzine fumarate reference substance oxbitzine fumarate reference substance
  • impurity A reference substance impurity A reference substance
  • impurity C reference substance impurity C reference substance
  • TEC triethyl citrate
  • capsule T content is the enteric-coated pellet preparation of oxitrazine fumarate prepared in Example 1, 100 mg
  • R oxitrazine hydroxypropyl- ⁇ cyclodextrin inclusion complex solution
  • Preparation method of R drug add an appropriate amount of hydroxypropyl- ⁇ cyclodextrin into 100 mL of purified water to dissolve, and then add 1 g of oxidazine fumarate raw material drug into water, stir and dissolve to obtain 10 mg/mL inclusion compound. 10 servings, 10mL each)
  • Blood sample collection before administration (0h) and after administration at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24h forelimb venous blood was collected from 3mL to 5mL of heparinized blood. in blood vessels.
  • the blood samples were centrifuged at 3000 r/min for 10 min within 15 min after collection to separate the plasma, and the plasma was transferred to a clean 2 mL EP tube to detect the content of oxidazine in the plasma.
  • the detection method of oxidazine in plasma is as follows:
  • the AUC 0- ⁇ of T drug (7977.234ug/L*h) was significantly higher than that of R drug (4182.582 ⁇ g/L*h), indicating that the enteric-coated micropill capsule prepared in Example 1 of the present invention has a stable release in vivo, and its bioavailability high.
  • the preparation provided by the present invention is an enteric-coated micro-pellet capsule, and is well absorbed in the duodenum, and the preparation needs to be released quickly after entering the intestinal tract.
  • enteric-coated materials whose dissolution pH is as close to the duodenal pH range as possible are selected as candidate materials.
  • Acrylic resin epoxy resin
  • HPMC-AS HPMC-AS
  • Opadry enteric 91 series PVAP
  • HPMCP HP-55
  • Cup 1 in group 1 can be completely dissolved, indicating that 5 mg of Eudragit L100-55 can be completely dissolved in 100 ml of release medium, but precipitation occurs in cup 2, and the amount of oxidazine fumarate measured in the solution is very small, which is reasonable It is inferred that they interact with each other, and the effect is strong.
  • groups 2, 3, and 4 also have different degrees of interaction, and the order of their strength is: Opadry (PVAP) > Acrylic resin (Udag L100-55) > HPMCP (HP-55) > HPMC- AS (LG). From the perspective of stability and formulation release risk, HPMC-AS is suitable for the enteric-coated pellet formulation of the present invention, followed by HPMCP.
  • the wetting agent ethanol concentration was designed to vary between 50% and 95% to prepare the pellets.
  • the optimal ethanol concentration was screened out with roundness and disintegration time as the inspection objects.
  • Table 7 the formulation and feeding were carried out, and the soft materials were manually prepared by using ethanol with concentrations of 75%, 60% and 50%, respectively, using an extrusion plate with a diameter of 0.9 mm and an extrusion speed of 30 rpm.
  • the pellets are prepared by adjusting the spheronization parameters according to the situation, and the prepared pellets are dried in a fluidized bed (the inlet air temperature and the material temperature are 35°C to 45°C) to obtain the plain pellets.
  • the roundness of the plain pills was observed, and the disintegration time was measured.
  • Table 7 The results are shown in Table 7.
  • Crospovidone (XL-10), Croscarmellose Sodium and Sodium Carboxymethyl Starch as the investigation objects, all use the conventional maximum dosage, and are used in combination with low-substituted hydroxypropyl cellulose to maintain the prescription
  • the dosage of other excipients remains unchanged, and the dosage of diluent is fine-tuned to make the drug loading of the pellets consistent.
  • 60% ethanol as a wetting agent, the soft material was manually prepared, the diameter of the extrusion plate was 0.9 mm, and the extrusion speed was 30 rpm.
  • the pellets are dried in a fluidized bed (the inlet air temperature is set at 45°C, and the material temperature is controlled at a temperature of 35°C to 45°C) to obtain plain pellets.
  • the fluidized bed air inlet fan rotates at 1200 rpm
  • the peristaltic pump rotates at 6-12 rpm
  • calculates the spraying speed of about 0.5-1.4 g/min and controls the atomization pressure of about 0.04Mpa to fully atomize the coating liquid
  • Material stability control is 3% weight gain at 35-45°C.
  • the fluidized bed air inlet fan rotates at 1200rpm
  • the peristaltic pump rotates at 6-12rpm
  • calculates the spraying speed of about 1.1g-1.7g/min and controls the atomization pressure of about 0.04Mpa to fully atomize
  • the temperature of the material is controlled to be 35°C to 45°C
  • the weight gain is 18% (theoretical feeding)
  • the coating recipe and process are the same.
  • the release and acid resistance were tested after the pellets were filled into capsules, and the results are shown in Table 8.
  • the barrier coating can prevent the API from interacting directly with the enteric coating material hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which affects the release and stability of the formulation. Only after the isolation coat completely wraps the drug-loaded pills and reaches a certain thickness, the direct contact or infiltration of API and HPMC-AS can be prevented. Incomplete or too thin coating of the isolation coat will lead to the interaction of API and HPMC-AS in the release medium in the case of local high concentrations, slowing down the release. The thicker the isolation coat (the greater the weight gain), the weaker the interaction, and HPMC itself also has the characteristics of non-ionic surface activity, which is beneficial to the release of the formulation. In addition, the acidity of the enteric coating material is the unstable factor (degradation) of the API, so the weight gain of the barrier coat is beneficial to the stability of the preparation-related substances.
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • the particle size of the plain pill is about 0.6-1.2mm, and the surface area is large. It needs a certain amount of coating to increase the weight to completely wrap the surface of the plain pill. According to the diameter of the plain pellets, the surface of the pellets can be completely covered by the isolation coat only when the coating weight gain is 6.8%. In this example, the weight gain was designed to be 7%, 15% and 19%, and the coating effect was investigated.
  • Hypromellose is selected as the isolation coat material
  • talcum powder is used as an anti-sticking agent (the dosage ratio is 4:1)
  • the rotational speed of the fluidized bed air inlet fan is controlled to be adjusted according to different batches, 1200 ⁇ 1800rpm, and the rotational speed of the peristaltic pump is 6 ⁇ 8.
  • the spraying speed is about 0.7 ⁇ 1.5g/min
  • the atomization pressure is controlled to be about 0.04 ⁇ 0.12Mpa to fully atomize the coating liquid
  • the material stability is controlled at 35 ⁇ 45°C.
  • the fluidized bed air inlet fan speed is 1200-1400rpm
  • the peristaltic pump speed is 6-12
  • the spray rate is about 0.8-1.3g/min
  • the atomization pressure is controlled at about 0.04-0.06Mpa.
  • Atomize the coating liquid the actual material temperature is controlled at 35°C to 42°C, and the weight gain is 18%. After the enteric-coated pellets were filled with capsules, the release and acid resistance were tested. The results are shown in Table 9.
  • Obitrazine fumarate is unstable in acidic conditions, and the enteric material is highly acidic, and the weight gain of the isolation coating affects the integrity and thickness of the isolation coating film.
  • the weight gain of the isolation coating is investigated, and the isolation coating that can effectively block the weight gain of oxidazine fumarate and enteric materials is screened out.
  • the main inspection items are content, related substances, acid resistance and release. The results are shown in Table 10.
  • the impurity C in the related substances of the barrier coat coating increased by 14.1% and 19.5%, and was not detected in 0 days.
  • the increase in the impurity C in March accelerated to 0.19%, and the growth rate was the same, and the stability was achieved. Require. Therefore, from the perspective of related substances, the isolation coat of 14.1% (according to 15% of the material) and above can effectively block the enteric coating and protect the oxbitzine fumarate.
  • the rotational speed of the fluidized bed air inlet fan is 1200 ⁇ 1400rpm
  • the rotational speed of the peristaltic pump is 6 ⁇ 12rpm
  • the spray rate is about 0.8 ⁇ 1.2g/min
  • the atomization pressure is controlled to be about 0.03 ⁇ 0.04Mpa to fully atomize the coating liquid.
  • the actual material temperature is controlled as 35°C ⁇ 40°C.
  • the acid resistance and release of enteric-coated pellets were tested, and the results are shown in Table 11.
  • the weight gain of the enteric coating is 18%, which can ensure that the release of the enteric-coated micro-pill capsules of oxynitzine fumarate reaches the development target;

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une pilule enrobée entérique de fumarate d'obizidine, son procédé de préparation et son utilisation dans la préparation d'un médicament pour la prévention et/ou le traitement de tumeurs.
PCT/CN2021/108360 2020-08-07 2021-07-26 Pilule enrobée entérique de fumarate d'obizidine, son procédé de préparation et son utilisation WO2022028264A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP21853332.1A EP4193991A1 (fr) 2020-08-07 2021-07-26 Pilule enrobée entérique de fumarate d'obizidine, son procédé de préparation et son utilisation
JP2023532638A JP7448275B2 (ja) 2020-08-07 2021-07-26 オービットアジンフマル酸塩腸溶性ペレット、その調製方法及び使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010789585.5A CN111743876B (zh) 2020-08-07 2020-08-07 富马酸奥比特嗪肠溶微丸及其制备方法和用途
CN202010789585.5 2020-08-07

Publications (1)

Publication Number Publication Date
WO2022028264A1 true WO2022028264A1 (fr) 2022-02-10

Family

ID=72713290

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/108360 WO2022028264A1 (fr) 2020-08-07 2021-07-26 Pilule enrobée entérique de fumarate d'obizidine, son procédé de préparation et son utilisation

Country Status (4)

Country Link
EP (1) EP4193991A1 (fr)
JP (1) JP7448275B2 (fr)
CN (1) CN111743876B (fr)
WO (1) WO2022028264A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111743876A (zh) * 2020-08-07 2020-10-09 深圳市真兴医药技术有限公司 富马酸奥比特嗪肠溶微丸及其制备方法和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101503394A (zh) * 2009-03-11 2009-08-12 深圳市湘雅生物医药研究院 高哌嗪乙酰肼类衍生物及其制备方法和用途
CN101502517A (zh) * 2008-09-04 2009-08-12 山东淄博新达制药有限公司 格列吡嗪肠溶缓释制剂组合物及其制备方法
WO2010102513A1 (fr) 2009-03-11 2010-09-16 深圳市湘雅生物医药研究院 Dérivés d'acétyl-hydrazide d'homopipérazine, leur procédé de préparation et leurs utilisations
CN105085421A (zh) * 2015-07-24 2015-11-25 深圳市湘雅生物医药研究院 奥比特嗪-富马酸盐、水合物、晶型及其制备方法
CN111743876A (zh) * 2020-08-07 2020-10-09 深圳市真兴医药技术有限公司 富马酸奥比特嗪肠溶微丸及其制备方法和用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101987835A (zh) * 2009-07-29 2011-03-23 深圳市湘雅生物医药研究院 高哌嗪乙酰肼类衍生物
CN101565409B (zh) * 2009-03-20 2011-09-07 深圳市湘雅生物医药研究院 哌嗪或高哌嗪草酰肼类化合物及其制备方法和用途
US10561667B2 (en) * 2015-07-24 2020-02-18 Shenzhen Zhenxing Medical Technology Co., Ltd. Orbit azine-fumarate, hydrate, crystal form and preparation method therefor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101502517A (zh) * 2008-09-04 2009-08-12 山东淄博新达制药有限公司 格列吡嗪肠溶缓释制剂组合物及其制备方法
CN101503394A (zh) * 2009-03-11 2009-08-12 深圳市湘雅生物医药研究院 高哌嗪乙酰肼类衍生物及其制备方法和用途
WO2010102513A1 (fr) 2009-03-11 2010-09-16 深圳市湘雅生物医药研究院 Dérivés d'acétyl-hydrazide d'homopipérazine, leur procédé de préparation et leurs utilisations
CN105085421A (zh) * 2015-07-24 2015-11-25 深圳市湘雅生物医药研究院 奥比特嗪-富马酸盐、水合物、晶型及其制备方法
CN111743876A (zh) * 2020-08-07 2020-10-09 深圳市真兴医药技术有限公司 富马酸奥比特嗪肠溶微丸及其制备方法和用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Chinese Pharmacopoeia", 2015
LIU SHUJIE, YU MIN;WANG YU;HUANG SHU-JIA;DAN MO;LI ZUO-GANG;GENG XING-CHAO;ZHANG HE-ZHAN;YANG JIN-BO;LIU LI: "Establishment and validation of UPLC － MS / MS method for determination of an innovative antitumor drug SM － 1 in plasma of Beagle dogs", CHINESE JOURNAL OF NEW DRUGS, GAI-KAN BIANJIBU, BEIJING, CN, vol. 29, no. 12, 30 June 2020 (2020-06-30), CN , pages 1349 - 1354, XP055895473, ISSN: 1003-3734 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111743876A (zh) * 2020-08-07 2020-10-09 深圳市真兴医药技术有限公司 富马酸奥比特嗪肠溶微丸及其制备方法和用途
CN111743876B (zh) * 2020-08-07 2022-05-10 深圳市真兴医药技术有限公司 富马酸奥比特嗪肠溶微丸及其制备方法和用途

Also Published As

Publication number Publication date
CN111743876B (zh) 2022-05-10
JP7448275B2 (ja) 2024-03-12
CN111743876A (zh) 2020-10-09
EP4193991A1 (fr) 2023-06-14
JP2023537647A (ja) 2023-09-04

Similar Documents

Publication Publication Date Title
US10973769B2 (en) Muco-adhesive, controlled release formulations of levodopa and/or esters of levodopa and uses thereof
JP6356215B2 (ja) エベロリムスを含む医薬組成物
AU2005324132A1 (en) Solid, orally applicable pharmaceutical administration forms containing rivaroxaban having modified release
CA2529746A1 (fr) Composition orale a liberation prolongee
CN101299993A (zh) 用于给药难溶的药学活性剂的羧烷基纤维素酯
WO2010078429A1 (fr) Formes galéniques et procédés de fabrication de celles-ci
JP5479909B2 (ja) 新規製剤
WO2011002857A2 (fr) Formulations de comprimé de 3- cyanoquinoline et leurs utilisations
WO2018108157A1 (fr) Composition pharmaceutique à libération prolongée / contrôlée de rucaparib pour la voie orale, et utilisation de cette dernière
JP5013871B2 (ja) 経口徐放性医薬組成物
WO2022028264A1 (fr) Pilule enrobée entérique de fumarate d'obizidine, son procédé de préparation et son utilisation
RU2484816C2 (ru) Фармацевтические композиции реина или диацереина
WO1990013286A1 (fr) Preparation orale pouvant etre liberee dans une region appropriee de l'intestin
CN112999229A (zh) 一种包含布地奈德的口服药物组合物
CN112569190B (zh) 一种白头翁皂苷b4的口服给药制剂及其制备方法
JP3122478B2 (ja) 下部消化管放出型経口製剤
WO2022061058A1 (fr) Formes posologiques multiparticulaires comprenant de la deutétrabenazine
KR101761983B1 (ko) 구강내 속붕해 필름 조성물 및 그 제조방법
WO2015196956A1 (fr) Composition à libération prolongée de métoprolol et son procédé de préparation
CN117442577B (zh) 一种坎地沙坦酯微片及制备方法和应用
US20100034887A1 (en) Bursting Pellets
WO2021175274A1 (fr) Composition d'amélioration de la dissolution de l'olaparib
WO2002064133A1 (fr) Preparations permettant de reguler une concentration dans le sang
EP4240332A1 (fr) Composition pharmaceutique comprenant du méloxicam
WO2021209945A1 (fr) Procédés et compositions de traitement du cancer de la prostate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21853332

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2023532638

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021853332

Country of ref document: EP

Effective date: 20230307